TW201032807A - Treating agent for glaucoma comprising Rho kinase inhibitor and prostaglandin - Google Patents

Treating agent for glaucoma comprising Rho kinase inhibitor and prostaglandin Download PDF

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TW201032807A
TW201032807A TW099103157A TW99103157A TW201032807A TW 201032807 A TW201032807 A TW 201032807A TW 099103157 A TW099103157 A TW 099103157A TW 99103157 A TW99103157 A TW 99103157A TW 201032807 A TW201032807 A TW 201032807A
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rho kinase
kinase inhibitor
prostaglandin
glaucoma
prostaglandins
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TW099103157A
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TWI350170B (en
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Tadashi Nakajima
Takeshi Matsugi
Hideaki Hara
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Santen Pharmaceutical Co Ltd
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Description

201032807 玖、發明說明： 【發明所屬之技術領域】 本發明爲有關由Rho激酶抑制劑及前列腺素類而成之 青光眼治療劑。 【先前技術】 青光眼爲由種種病因而眼壓上昇、眼球内部組織（網 膜、視神經等）受障害所致失明之有危險性之難治性眼疾 病。青光眼之治療方法一般爲降眼壓療法，其代表有薬物 0 療法，雷射治療法，手術療法等。 藥物療法可用交感神經刺激藥（腎上腺素等非選擇性刺 激藥、阿布拉苦羅尼定等0：2刺激藥）、交感神經遮斷藥（記 莫羅、別府諾羅等Θ遮斷藥、鹽酸部那坐新等αΐ遮斷 藥）、副交感神經激動藥（毛果藝香鹼等）、碳酸酐酶抑制 劑（鹽酸杜坐醯胺等）、前列腺素類（異丙基吳諾普羅史 酮、拉他諾普羅史脫、多拉波普羅史脫、必馬多普羅史脫 等）等藥物。 Q 最近，作爲基於新作用機制之青光眼治療藥，發現Rho 激酶抑制劑（國際公開W0 00 /09 1 62號號。Rho激酶抑制劑 可促進從纖維柱帶流出經路之房水流出而使降眼壓已在 非專利文獻1揭示，且其作用機制爲在纖維柱帶細胞之細 胞骨架之再構築乃在I0VS，42 ( 1 )，1 37 - 144( 2001 )及 10 VS，42 ( 5) ,1029 - 1 037 ( 2001 )提示，故以青光眼治療目 的，將具有降眼壓作用之藥劑組合使用，乃以前就已硏 究，已有若干報告。例如在日本專利第2726672號公報， 201032807 有交感神經遮斷藥與前列腺素類之組合投與之報告。又在 國際公開W0O2/38 1 58號，揭示將若干具有降眼壓作用之 藥劑組合在眼投與之青光眼治療方法。 但在任何報告從無有關Rho激酶抑制劑之記載，當然也 無其與前列腺素類之倂用效果之記載。 如上所述，至今從無有關將Rho激酶抑制劑與前列腺素 類組合時之青光眼之治療效果之硏究及報告。 【發明內容】 將Rho激酶抑制劑與前列腺素類組合之青光眼治療劑 之有用性找出爲非常有趣之課題。 本發明者將Rho激酶抑制劑與前列腺素類之組合之效 果致力硏究之結果，發現將這些藥劑組合，則與各藥劑單 獨使用時比較，可使降眼壓作用増強及/或改善其作用之 持續性，完成本發明。詳細試驗方法及其結果容後述藥理 試驗説明，Rho激酶抑制劑與前列腺素類組合，則發現降 眼壓作用之顯著増強及/或其作用之持續性顯著改善。 本發明爲Rho激酶抑制劑與前列腺素類之組合而成之 青光眼治療劑，互相使其作用補全及/或増強。 投與形態可爲將Rho激酶抑制劑與前列腺素類分別以 製劑之形投與，即可倂用投與，又可將這些以1製劑化之 形，也即以合劑之形投與。 本發明所謂之Rho激酶抑制劑及前列腺素類也包括鹽 之形態》若這些化合物含有胺基等鹼性基時，可成鹽酸、 硝酸等無機酸之鹽或草酸、丁二酸、乙酸等有機酸之鹽， 若含有羧基等酸性基時可成鈉、鉀等鹼金屬鹽、鈣等鹸土 修正頁 201032807 金饜鹽。 又本發明所謂之Rho激酶抑制劑及前列腺素類也包括 酯等衍生物》酯之具體例可爲甲酯、乙醋、異丙酯等烷酯。 本發明以Rho激酶抑制劑與前列腺素類之組合來治療 青光眼爲特徴。 本發明所謂之Rho激酶抑制劑乃指抑制隨Rho之活性化 而活性化之絲胺酸/酥胺酸激酶之化合物。例如，R0K α (ROCK- II)，pMOROCKUOK^S，R0CK-I)及其它抑制具有 © 絲胺酸/酥胺酸激酶活性之蛋白質之化合物。Rho激酶抑 制劑之具體例有在W098/064 3及W000/09162揭示之（R)-反-N-(吡啶-4-基）-4-(1-胺乙基）環己烷羧醯胺， (R)( + )- N-(lH-吡咯并[2,3-b]吡啶-4-基）-4-(1-胺乙基） 苄醯胺等Rho激酶抑制劑及W097 / 23222及Nature， 389,990- 994 ( 1 997 )揭示之1-(5-異唾啉磺醯基）高哌啶， 1-(5 -異喹啉磺醢基）-2_甲基哌畊等Rho激酶抑制劑， W001/56988揭示之（1-苄基吡咯啶-3-基）（1H-吲唑-5-基） ® 胺等Rho激酶抑制劑，W002 / 100833揭示之（1-苄基哌啶 -4-基）（1H-吲唑-5-基）胺等 Rho激酶抑制劑， W002/076976 揭示之 N-[2-(4-氟苯基）·6,7-二甲氧基-4-喹唑啉基]-Ν·(1Η-吲唑-5-基）胺等Rho激酶抑制劑， W002/ 076977 揭示之 Ν-4-(1Η-吲唑-5-基）-6,7-二甲氧基 -N-2-吡啶-4-基-喹唑啉-2,4-二胺等Rho激酶抑制劑， W0 99/6 40 11揭示之4 -甲基- 5-(2 -甲基-[1，4]二吖庚因 -1-磺醯基）異喹啉等Rho激酶抑制劑。 201032807 至於前列腺素類只要具有降眼壓作用而對青光眼治療 有用即可。具有降眼壓作用之前列腺素類之具體例可爲特 開昭59-1418揭示之前列腺素類（尤其是如前列腺素F20： 等天然前列腺素）、特表平3-50102 5揭示之拉他諾普羅史 脫等前列腺素類，特開平2-108揭示之異丙基吳諾普羅史 酮等前列腺素類，特表平8-501310揭示之必馬多普羅史 脫等前列腺素類，特開平10-182465揭示之多拉波普羅史 脫等前列腺素類等例示，尤其宜用當作青光眼治療藥銷售 〇 之拉他諾普羅史脫、異丙基吳諾普羅史酮、必馬多普羅史 ' 脫或多拉波普羅史脫。 本發明中青光眼可爲原發性開放隅角青光眼，正常眼壓 青光眼，房水産生過多青光眼，高眼壓症，急性閉塞隅角 青光眼，慢性閉塞隅角青光眼，混合型青光眼，類固醇青 光眼，類澱青光眼，血管新生青光眼，悪性青光眼水晶體 之囊性青光眼，平坦彩虹症候組等之例示。 實施本發明之製劑可爲將Rho激酶抑制劑與前列腺素 〇 類分別處方之2製劑，也可爲將各成分配合各1製劑。這 些製劑化無需特別技術，可用汎用技術來製劑化。投與方 法宜眼局部投與，其劑型宜點眼劑或眼軟膏。 將Rho激酶抑制劑與前列腺素與分別製劑化時，可依各 公知方法調製製劑。例如，Rho激酶抑制劑之製劑可參照 上述國際公開專利公報（W0 00/09162，W0 97 / 23222)記載之 製劑例來調製。前列腺素類之製劑可參照上述日本公開專 利公報或日本公表專利公報（特開昭59-1418，特表平 201032807 3-501025，特開平 2-108，特表平 8-501310，特開平 10-18 246 5)記載之製劑例來調製，尤其是已當作青光眼治 療藥銷售之拉他諾普羅史脫、異丙基吳諾普羅史萌、必馬 多普羅史脫、多拉波普羅史脫等可用市售之製劑。 欲調製將Rho激酶抑制劑與前列腺素類配合之製劑時， 也可依公知之方法調製。例如點眼劑可將氯化鈉、濃甘油 ! 等之等張化劑，磷酸鈉、乙酸鈉等緩衝劑、聚氧乙烯單油 酸山梨糖酯、硬脂酸聚乙二醇40、聚氧乙烯硬化蓖麻油 〇 等界面活性劑，檸檬酸鈉、乙二胺四乙酸鈉等安定化劑， 苄烷氯化銨、對羥苄酸酯等防腐劑等視必要而使用調製。 pH只要爲眼科製劑容爲之範圍内即可，宜爲pH4〜8之範 圍內。將其製劑例之一部分在後述實施例記載，但此製劑 例乃供參考，非限定本發明之範圍。
Rho激酶抑制劑及前列腺素類之投與量可依患者之症 狀、年齡、劑型、投與經路等來決定。以點眼投與爲例， 以下簡單説明之》Rho激酶抑制劑之投與量依藥物種類而 ® 異，通常1日之投與量爲0.025〜100 00 ;zg之範圍內，可 1曰分i回或數回投與，這些用量可依患者之年齡、症狀 等適宜増減。 前列腺素類之投與量依藥物種類而異，通常1日之投與 量爲0.1〜1000 之範圍內，可1日分1回或數回投與。 更具體而言，拉他諾普羅史脫時1日量1〜5/zg、異丙基 吳諾普羅史酮時1日量30〜3 00 vg爲通常使用’這些用 量可依患者之年齡、症狀等適宜増減。又其他前列腺素類 201032807 也可依同樣基準，將其用量決定。 這些投與量爲將Rho激酶抑制劑與前列腺素類倂用投 與時適用，但在將Rho激酶抑制劑與前列腺素類配合之製 劑投與時，調製使1日之投與量呈上述各成分之量或其以 下地將配合比率適宜選擇之製劑，將此配合製劑分1日1 回或數回投與。 【實施方式】
以下作爲實施例列示製劑例及藥理試驗，但這些爲使本 發明更能理解者，非限定本發明之範圍。 [製劑例] 本發明中Rho激酶抑制劑（（R)_( + )_N_(1H_吡咯并 [2,3-b]耻陡-4-基）·4·(1•胺乙基）苄醯胺二鹽酸鹽）與前 列腺素類類（異丙基吳諾普羅史酮）配合之點眼劑之一般 製劑例如下。 點眼劑（100mL中） ❹ 苄醯胺二鹽酸鹽
0 . 06g 異丙基吳諾普羅史酮 0 . 2g 0 . 25g 0.0〇5g 適量 適量 適量 硼酸 濃甘油 苄烷氯化銨 稀鹽酸 氫氧化鈉 精製水 -10- 201032807 上述處方中，將Rho激酶抑制劑及前列腺素類之種類及 量改變，又將添加劑之量適宜變化，則可調製所望組合及 所望濃度之點眼液。 [藥理試驗] 爲調査Rho激酶抑制劑與前列腺素類之組合之有用 性，於日本白兔（系統：〗W,性別：雄性）或食蟹猴（性別：雄 性）將Rho激酶抑制劑與前列腺素類倂用投與時之降眼壓 效果予以檢討。Rho激酶抑制劑乃用（R)-( + )-N-(lH-吡咯 D 并[2, 3-b]吡啶-4-基）-4-(1-胺乙基）苄醯胺二鹽酸鹽[化 合物A]或1-(5 -異喹啉磺醯基）高哌啶二鹽酸鹽[化合物 B]，前列腺素類乃用異丙基吳諾普羅史酮或拉他諾普羅史 脫。 (被驗化合物溶液之調製） 1 . Rho激酶抑制劑溶液之調製 將Rho激酶抑制劑溶在生理食鹽水後，以氫氧化鈉中和 (PH6.0〜7.0)來調製所望濃度之Rho激酶抑制劑溶液。 〇 2.前列腺素類溶液之調製 將市售之異丙基吳諾普羅史酮點眼液（商品名：列斯久 拉點眼液）或拉他諾普羅史脫點眼液（商品名：奇砂拉坦點 眼液）就此，或以生理食鹽水稀釋，來調製所望濃度之前 列腺素類溶液。 (試驗方法） 檢討將Rho激酶抑制劑與前列腺素類倂用投與時之降眼壓 效果。作爲比較對照，也檢討Rho激酶抑制劑單獨投與或 201032807 前列腺素類單獨投與時之降眼壓效果。對照只投與基劑（生 理食鹽水）》又實驗動物使用日本白兔（系統：jw，性別：雄性） 或食蟹猴（性別：雄性）。 (投與方法及測定方法） 1. Rho激酶抑制劑與前列腺素類之倂用投與 1) 將0.4%鹽酸氧普羅卡因點眼液在實驗動物之兩眼點眼 一滴來局部麻酔。 2) 被驗化合物溶液投與即前測定眼壓，當作初期眼壓。 O 3)Rho激酶抑制劑溶液在實驗動物之一眼點眼（對側眼無 處置）。不可能同時將前列腺素類溶液點眼，故稍隔時間 (約5分）而將前列腺素類溶液在同一眼點眼。 4 )Rho激酶抑制劑溶液點眼之2小時、4小時、6小時及8 小時後，將0.4%鹽酸氧普羅卡因點眼液在兩眼點眼一滴， 局部麻酔後，測定眼壓。眼壓測定3回，其平均値列示於 結果。 至於以下試驗例所示之試驗2，當作2小時、4小時及 ® 6小時後之眼壓之測定。 2. Rho激酶抑制劑單獨投與 以前列腺素類溶液代替生理食鹽水，其他仿上述倂用投 與試驗之相同方法試驗。 3. 前列腺素類單獨投與 以Rho激酶抑制劑溶液代替生理食鹽水，其他仿上述併 用投與試驗之相同方法試驗。 4. 對照 -12- 201032807 以Rho激酶抑制劑溶液及前列腺素類溶液代替生理食 鹽水，其他仿上述倂用投與試驗相同方法試驗。 (試驗1〜4 ) 各試驗所用之Rho激酶抑制劑溶液、前列腺素類溶液及 • . ' ' ‘ . . · . . ... * .. 實驗動物如表1所示。 依上述（試驗方法）及（投與方法及測定方法），實施試驗 1 ^-0·/ 4 〇
-13- 201032807 表1
Rho激酶抑制劑溶液 前列腺素類溶液 實驗動物 1 0.3%化合物A溶液 (50^1) 0.06%異丙基吳諾普羅史酮溶 液(50以1) 兔(一組4隻） 試驗2 献合物B溶液 (50“1) 0.06%異丙基吳諾普羅史酮溶 液(50//1) 兔(一Μ 5隻） 試驗3 0.1%化合物A溶液 (20/zl) 0.005%拉他諾普羅史脫溶液 (20//1) 食蟹猴(，3隻） 試驗4 m匕合物b溶液 (20"1) 0.005%拉他諾普羅史脫溶液 (20//1) 食蟹猴(一組3隻） (結果及考察） Ο
試驗1之結果如第1圖，試驗2之結果如第2圖，試驗 3之結果如第3圖，試驗4之結果如第4圖。眼壓乃示從 初期眼壓之變化値。 如第1圖、第2圖、第3圖及第4圖所示，Rho激酶抑 制劑與前列腺素類之併用組比藥劑單獨投與組，也即Rho 激酶抑制劑投與組或前列腺素類投與組均優之降眼壓作 用，且改善其作用之持續性。由上述確認將Rho激酶抑制 劑與前列腺素類組合，則可得更強降眼壓效果及/或持續 性之改善。 産業h利用可能性 將Rho激酶抑制劑與前列腺素類組合投與在眼，則可得 增強降眼壓效果及/或持續性之改善。故此組合可當作青 光眼治療劑。 【圖式簡單說明】 第1圖乃示各投與組之眼壓之經時變化。眼壓以從初期 眼壓之變化値表示。口爲化合物A與異丙基吳諾普羅史酮 -14- 201032807 之倂用投與組，爲化合物A單獨投與組，△爲異丙基吳 諾普羅史酮單獨投與組，〇爲對照組。 第2圖乃示各投與組之眼壓之經時變化。眼壓以從初期 眼壓之變化値表示》口爲化合物B與異丙基吳諾普羅史酮 .· . . ........... 之倂用投與組，爲化合物B單獨投與組，△爲異丙基吳 諾普羅史酮單獨投與組，〇爲對照組。 第3圖乃示各投與組之眼壓之經時變化。眼壓以從初期 眼壓之變化値表示。口爲化合物A與拉他諾普羅史脫之倂 0 用投與組，爲化合物A單獨投與組，△爲拉他諾普羅史 脫單獨投與組，〇爲對照組。 第4圖乃示各投與組之眼壓之經時變化。眼壓以從初期眼 壓之變化値表示。口爲化合物B與拉他諾普羅史脫之倂用 投與組，爲化合物B單獨投舆組，△爲拉他諾普蘿史脫 單獨投與組，〇爲對照組。 ❿ -15-

Claims (1)

  1. 201032807 十、申請專利範圍： 1 ·一種青光眼治療劑，其係由Rho激酶抑制劑與前列腺素 類之組合而成，但Rho激酶抑制劑爲（R)-( + )-N-(lH-吡咯 并[2,3-b]吡啶-4-基）-4-(1-胺乙基）苄醯胺及前列腺素類 爲拉他諾普羅史脫（latanoprost)之組合除外。 2 .—種青光眼治療劑，其特徴爲由Rho激酶抑制劑與前列 腺素類之組合而成，而互相輔助及/或增強其作用，但Rho 激酶抑制劑爲（R)_( + )-N-(lH-吡咯并[2,3-b]吡啶-4-基）-4-(1-胺乙基）苄醯胺及前列腺素類爲拉他諾普羅史脫 (latanoprost)之組合除外。 3. 如申請專利範圍第1或2項之青光眼治療劑，其中Rho 激酶抑制劑爲（R)-反-N-(吡啶-4-基）-4-(1-胺乙基）環己烷 羧醯胺、（R)-( + )-N-(lH-吡咯并[2,3-b]吡啶-4-基）-4-(1-胺乙基）苄醯胺、1-(5-異唾啉磺醯基）高哌啶或1-(5-異喹 啉磺醯基）-2-甲基哌畊，前列腺素類爲異丙基吳諾普羅史 酮（unoprostone)、多拉波普羅史脫（travoprost)或必馬多 普羅史脫（bimatoprost)。 4. 如申請專利範圍第1或2項之青光眼治療劑，其中Rho 激酶抑制劑爲（R)-反-N-(吡啶-4-基）-4-(1-胺乙基）環己烷 羧醯胺、1-(5-異喹啉磺醯基）高哌啶或1-(5-異唾啉磺醯 基）-2-甲基哌畊，前列腺素類爲異丙基吳諾普羅史酮 (unoprostone)、拉他諾普羅史脫（latanoprost)、多拉波普 羅史脫（travoprost)或必馬多普羅史脫（bimatoprost)。
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